title: Efficacy of the dual PI3K and mTOR inhibitor NVP-BEZ235 in combination with nilotinib against BCR-ABL-positive leukemia cells involves the ABL kinase domain mutation.
abstract: Imatinib, an ABL tyrosine kinase inhibitor (TKI), has shown clinical efficacy against chronic myeloid leukemia (CML). However, a substantial number of patients develop resistance to imatinib treatment due to the emergence of clones carrying mutations in the protein BCR-ABL. The phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway regulates various processes, including cell proliferation, cell survival, and antiapoptosis activity. In this study, we investigated the efficacy of NVP-BEZ235, a dual PI3K and mTOR inhibitor, using BCR-ABL-positive cell lines. Treatment with NVP-BEZ235 for 48 h inhibited cell growth and induced apoptosis. The phosphorylation of the AKT kinase, eukaryotic initiation factor 4-binding protein 1 (4E-BP1), and p70 S6 kinase were decreased after NVP-BEZ235 treatment. The combination of NVP-BEZ235 with a BCR-ABL kinase inhibitor, imatinib, or nilotinib, induced a more pronounced colony growth inhibition, whereas the combination of NVP-BEZ235 and nilotinib was more effective in inducing apoptosis and reducing the phosphorylation of AKT, 4E-BP1, and S6 kinase. NVP-BEZ235 in combination with nilotinib also inhibited tumor growth in a xenograft model and inhibited the growth of primary T315I mutant cells and ponatinib-resistant cells. Taken together, these results suggest that administration of the dual PI3K and mTOR inhibitor NVP-BEZ235 may be an effective strategy against BCR-ABL mutant cells and may enhance the cytotoxic effects of nilotinib in ABL TKI-resistant BCR-ABL mutant cells.
authors.affiliation: First Department of Internal Medicine; Tokyo Medical University; Tokyo, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Okabe
authors.affiliation: First Department of Internal Medicine; Tokyo Medical University; Tokyo, Japan.
authors.forename: Tetsuzo
authors.initials: T
authors.lastname: Tauchi
authors.affiliation: First Department of Internal Medicine; Tokyo Medical University; Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: First Department of Internal Medicine; Tokyo Medical University; Tokyo, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kitahara
authors.affiliation: Division of Hematology, Respiratory Medicine and Oncology; Department of Internal Medicine; Faculty of Medicine; Saga University; Saga, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Kimura
authors.affiliation: Department of Transfusion Medicine and Cell Therapy; Kyoto University Hospital; Kyoto, Japan.
authors.forename: Taira
authors.initials: T
authors.lastname: Maekawa
authors.affiliation: First Department of Internal Medicine; Tokyo Medical University; Tokyo, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Ohyashiki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics; D064593:Heterografts; D006801:Humans; D000068877:Imatinib Mesylate; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D011804:Quinolines; D000068877:Imatinib Mesylate; C546842:MTOR protein, human; D016044:Fusion Proteins, bcr-abl; D058570:TOR Serine-Threonine Kinases; C498826:nilotinib; C531198:dactolisib
keywords: BCR-ABL mutation; NVP-BEZ235; PI3K; chronic myeloid leukemia; mTOR; nilotinib; ponatinib resistance